The human macular retina is a remarkably specialized neural structure subserving high visual sensitivity, acuity and color perception. The macula is also a critical locus of blinding retinal degenerative disease and thus the major target for emerging restorative therapies. Normal macular function arises from multiple, anatomically and functionally distinct retinal microcircuits that link the eye to the brain. However the identity of the neural cell types, visual pathways and the underlying synaptic mechanisms for macular spatial and color-coding are poorly understood. The long-term goal is to determine the visual and synaptic physiology of morphologically identified visual pathways arising from the macula in a non-human primate model. The goal for this project period is to use newly developed patch clamp recording methods applied to the in vitro macula of the macaque monkey to identify the synaptic mechanisms that generate parallel pathways for form (high resolution, non-color coding) and color vision (separate 'red-green' and 'blue-yellow' color-coding). Aim 1 will directly determine the roles that excitation and inhibition play in transmitting long- (L) and middle- (M) wavelength cone signals to the midget ganglion cell receptive field. We will test the hypothesis that red-green and non- color signals are segregated to distinct midget cell subpopulations and that inner retinal inhibitory pathways are critical for the establishment of red-green color-coding. Aim 2 will determine the role that excitation and inhibition play in creating the unique receptive field structure of the small bi-stratified 'blue-yellow' ganglion cell. We will test the hypothesis that parallel excitatory ON and OFF cone bipolar inputs establish the basic color-coding circuitry. Aim 3 will determine the receptive field structure and cone inputs of two other recently identified but little understood visual pathways that utilize the sparse short (S) wavelength sensitive cones: the large bistratified blue-ON, and the sparse mono-stratified blue-OFF cells. The experimental approach for these three aims will be to make whole cell recordings from morphologically identified ganglion cells in the macular-raphe region and combine cone type-selective stimuli, voltage clamp-conductance analysis and pharmacological methods to determine how excitatory and inhibitory inputs from the L, M and S cone types determine the ganglion cell chromatic response and receptive field structure. To identify and target the rarely recorded large bi-stratified and sparse mono-stratified types we will use retrograde photodynamic staining in vitro from tracer injections placed in the lateral geniculate nucleus. The proposed project will provide the first analysis of how excitation and inhibition combine to generate the unique receptive field properties of the primate red-green and achromatic midget pathways and the diverse blue-yellow S-cone pathways. Our results will advance understanding of how the neural cell types of the macular retina initiate human form and color vision and will contribute to the development of molecular-based strategies for restoring macular function at the ganglion cell level. PUBLIC HEALTH RELEVANCE: The retinal macula, a crucial locus subserving high acuity and color perception at the start of the human visual process, is particularly vulnerable to blinding diseases. A major goal in retinal research are therapies that will reestablish visual processing in surviving cells that link the retina to the visual brain, yet the precise cells and circuits by which specialized macular neurons achieves such remarkable visual performance are poorly understood. The proposed research will use a novel, in vitro non-human primate model of the macula to identify and advance our understanding of the cell types and critical synaptic mechanisms that give rise to distinct spatial and color-coding visual pathways and will provide fundamental information for the development of molecular strategies to restore sight in degenerative retinal disease.